PROJECT SUMMARY/ABSTRACT: This is a K23 award application for Dr. Melissa Cortez, a neurologist and young investigator pursuing patient- oriented clinical research on sensory and autonomic dysfunction in post-traumatic headache (PTH). A K23 award will provide her with the means to acquire critical skills in three key career development areas: biostatistics, signal processing, and visual function testing (visual psychophysics). By acquiring these skills, Dr. Cortez will fulfill her career goal of becoming an independent investigator in the field of autonomic neurology. To pursue this goal, Dr. Cortez has assembled the mentoring team of Drs. KC Brennan (primary mentor), a systems neurosci- entist with expertise in circuit dysfunction of headache and traumatic brain injury (TBI), and Kathleen Digre (co- mentor), a neuro-ophthalmologist with expertise in photophobia and pupillary function. Complementing them is a three-person Advisory Committee with authorities in biostatistics, autonomic neurophysiology, and visual psy- chophysics. PTH is a notoriously disabling and treatment refractory chronic pain condition, and is the most common conse- quence of TBI. With the rising incidence of TBI, PTH represents a critically important, actionable public health issue, in which objective diagnostic and disease progression measures are needed. Based on recent evidence and her own preliminary data, Dr. Cortez's central hypothesis is that photophobia in PTH corresponds to objec- tive changes in pupillary autonomic function that are associated with an increased risk of persistent symptoms. She will test this hypothesis by evaluating pupillary function in PTH subjects with photophobia (Aim 1) and de- termining whether these changes predict poor recovery (Aim 2). She will also evaluate whether PTH-related photophobia is worse when exposed to specific colors of light (Aim 3). If successful, this work will lead to much needed objective measures of PTH disease burden, enabling early identification and individually targeted inter- ventions for PTH patients most at risk of prolonged symptoms. The proposed research is significant because PTH remains poorly understood and is a disorder where disease specific treatments are lacking. The proposed research is innovative because it combines sensory and auto- nomic testing to better understand and conceptualize the underlying disease mechanisms, as well as provide objectively measurable markers of disease with clinical utility for identifying patients at risk for disease progres- sion. Additionally, this work will lead to individually targeted, non-addictive therapies targeting sympathetic mod- ulation (vagal nerve stimulation, alpha and/or beta-blockade) and/or light-mitigation therapies for chronic PTH- related pain.